Adavosertib speeds cancer cells into the wall of mitotic catastrophe

A cancer cell is like a racecar, speeding through the process of
cellular replication. But it has to stop at the G2M cell cycle checkpoint,
where a race inspector called Wee1 checks it over for damage – cells with
intact DNA can continue, while cells with damaged DNA have to stick around for
repairs. The wait is worth it – there are curves ahead, and beyond the G2M
checkpoint, cells with damaged DNA explode against the wall of “mitotic
catastrophe.” But the thing is, we want cancer
cells to explode; we would rather they
speed through the G2M checkpoint without a Wee1 inspection and hit the wall of
mitotic catastrophe.

A University of Colorado Cancer Center study presented at the
American Association for Cancer Research (AACR) Annual Meeting 2019 suggests a
way to ensure that cancer cells with damaged DNA fly past G2M to their doom:
Blindfold the race inspector. By inhibiting the action of Wee1, cancer cells
blow right through the G2M checkpoint and are doomed by their damaged DNA to
mitotic catastrophe.

The Wee1 inhibitor adavosertib is used in a number of previous
and ongoing clinical trials. However, the drug’s effectiveness has
overall been promising but not perfect. The goal of the current study was to
test drugs in combination with adavosertib that might magnify its effect.
Specifically, the study hoped to find new combinations against pancreatic
cancer, which carries a prognosis of less than 7 percent 5-year survival.

“The way the grant was focused was to utilize the list of the drugs in the
NCI’s Cancer Therapy Evaluation Program (CTEP) and figure out what drugs might work
together with adavosertib against pancreatic tumors,” says Todd Pitts, PhD,
investigator at CU Cancer Center and assistant research professor in the CU
School of Medicine Division of Medical Oncology.

More broadly, the
work of the Pitts lab is at the cutting edge of a developing strategy against
cancer, namely the manipulation of cells’ ability to repair damaged DNA.
Commonly, DNA damage repair fixes mutations that could cause cancer. In other
words, “DNA damage repair is usually a good thing,” Pitts says. But when the
cells being repaired are cancer cells,
the “good” outcome switches from repair to destruction.

The most
successful combinations were adavosertib with irinotecan, navitoclax or
capecitabine.

“The Wee1 inhibitor and navitoclax have
overlapping toxicities, so we don’t believe that combination will move forward
clinically. But the irinotecan and capecitabine combos could move forward,”
Pitts says.

In fact, the group recently submitted a letter of intent to start a
clinical trial of combination adavosertib with capecitabine. “There will always
be some toxicity from a Wee1 inhibitor, but capecitabine is very well
tolerated, so we think adavosertib with capecitabine would be a well-tolerated
combination,” Pitts says.